Small molecule n-(alpha-peroxy) carbazole compounds and methods of use

ABSTRACT

The N-(α-peroxy)carbazole compounds described herein are useful for treating or preventing parasitic infections, bacterial infections, and cancer in subjects. The methods include administering an N-(α-peroxy)carbazole compound as described herein to a subject. Also described herein are methods for synthesizing N-(α-peroxy)carbazole compounds.

RELATED APPLICATION DATA

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/334,540, filed May 11, 2016.

TECHNICAL FIELD

The present invention relates to Small MoleculeN-(Alpha-Peroxy)Carbazole Compounds and Methods of Use

BACKGROUND OF THE INVENTION

The background of this invention will address Malarial Infection andResistance to Antimalarial Drugs and Compounds.

Malarial Infection

Malaria is an infectious disease caused by mosquito-borne Plasmodiumparasites affecting humans and other animals. The disease is prevalentin the tropical and subtropical regions of the world, particularly inareas around the equator. Malaria symptoms typically include chills,fever, fatigue, headaches, nausea or vomiting, and severe cases canresult in seizures, coma, or death. More than 200 million cases ofmalaria occur worldwide annually resulting in over 500,000 deaths eachyear. The disease is most commonly transmitted by a bite from aninfected Anopheles mosquito. The mosquito's saliva introduces theparasites into a person or animal's blood. Once in the bloodstream, theparasites travel to the liver where they mature and reproduce.

Malaria parasites belong to the genus Plasmodium (phylum Apicomplexa)and there are five known species of Plasmodium that can infect and bespread by humans. Plasmodium falciparum is the most common speciesidentified in humans, followed by P. vivax. Less commonly isolatedspecies are P. malariae, P. ovale, and P. knowlesi. P. falciparumgenerally accounts for the majority of deaths while P. vivax, P. ovale,and P. malariae usually causing a milder form of the disease.

Malaria infection develops via two phases: the first phase involves theliver, and the second phase involves the red blood cells. When aninfected mosquito bites an individual, the Plasmodium sporozoites fromthe mosquito's saliva enter the bloodstream, and migrate to the liver.Once the sporozoites infect the liver cells, they multiply over a periodof 8-30 days, eventually causing the infected liver cells to rupture.The parasites then return to the bloodstream, where they infect the redblood cells.

Because the malaria parasite resides for most of its human life cyclewithin the liver and blood cells, it is somewhat unnoticed by immunesurveillance, and is consequently protected from the body's immunesystem. However, circulating infected blood cells are destroyed in thespleen. In addition to this, the P. falciparum parasite secrete adhesiveproteins on the surface of the infected red blood cells, causing theblood cells to adhere to the walls of small blood vessels, furthersequestering the parasite from the general circulation and the spleen.

Resistance to Antimalarial Drugs

As yet, there are no effective vaccines against malaria, and control ofthe disease depends upon antimalarial drugs that kill parasites insidethe body. Diagnosis of malaria is made by microscopic examination ofblood, or with antigen-based rapid diagnostic tests. Once diagnosed, therecommended treatment is a combination of antimalarial medicationsincluding chloroquine, quinine, mefloquine, amodiaquin, primaquine,pyrimethamine, sulfonamides, sulfones, dihydrofolate reductaseinhibitors, and tetrandine, as well as others.

Recent decades have seen the emergence of parasites resistant tostandard drug therapies, and drug resistance is increasingly a problemin malaria treatment. Antimalarial drugs, such as cryptolepine andartemisinin, are often initially effective; however, the parasites thatcause the disease continuously evolve and become resistant to the drugs.Resistance is now common against most classes of antimalarial drugs.Treatment of resistant strains has become progressively more reliant ona few remaining drugs, and continued use of these drugs will increasethe incidence of resistance. P. falciparum in particular has developedresistance to nearly all of the currently available antimalarial drugs.

Compounds

Furthermore, many effective antimalarial drugs include an organicperoxide moiety, which generally includes two carbon atoms linked by theperoxide bond atoms. The known methods for constructing the organicperoxide bond are highly inefficient and ineffective. For example, onemethod for constructing the organic peroxide moiety includes thecoupling reaction of oxygen radicals to form a peroxide bond. The oxygenfree radicals are highly reactive, which makes unwanted side reactionsdifficult to control.

The known methods for constructing the organic peroxide moiety requireeither a special substrate or special conditions. Moreover, none of themcan be integrated with carbazole moeities and the classic peroxideoxidant to give N-(α-peroxy)carbazole.

SUMMARY OF THE INVENTION

N-(α-peroxy)carbazole compounds and derivatives thereof are provided,along with new methods of using and making the same. A class ofN-(α-peroxy)carbazole compounds and derivatives thereof as describedherein includes compounds of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein

is a single bond or a double bond; A¹, A² , A³, A⁴, A⁵ , A⁶ , A⁷ , andA⁸ are each independently selected from CR, CR₂, O, SO₂, N, and NR,wherein each R is selected from the group consisting of hydrogen,halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted orunsubstituted carbonyl, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedheteroalkenyl, substituted or unsubstituted heteroalkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocycloalkyl; and R⁹, R¹⁰ , and R¹¹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heteroalkenyl, substituted or unsubstitutedheteroalkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocycloalkyl. In this class ofcompounds, adjacent substituents can combine to form a substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heterocycloalkenyl.

Optionally, the compound has the following formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein R¹,R², R³, R⁴ , R⁵, R⁶, R⁷, and R⁸ are each independently selected fromhydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substitutedor unsubstituted carbonyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocycloalkyl; and R⁹, R¹⁰, and R¹¹ are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heteroalkenyl, substituted or unsubstitutedheteroalkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocycloalkyl. Optionally, R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and/or R⁸ can be hydrogen. R⁹ can optionally be asubstituted or unsubstituted alkyl.

Optionally, the compound has the following structure:

or a pharmaceutically acceptable salt or prodrug thereof. Optionally,the compound is selected from the group consisting of:

Optionally, the compound has the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein R¹,R², R³, R⁴ , R⁵ , R⁶, and R⁸ are each independently selected fromhydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substitutedor unsubstituted carbonyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocycloalkyl; and R⁷ is hydrogen, substituted orunsubstituted carbonyl, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedheteroalkenyl, substituted or unsubstituted heteroalkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocycloalkyl.

Optionally, the compound is:

Also described herein are compositions comprising a compound asdescribed herein and a pharmaceutically acceptable carrier.

Further described herein are methods of treating or preventing aparasitic infection in a subject. A method of treating or preventing aparasitic infection in a subject comprises administering to a subject aneffective amount of a compound or a composition as described herein.Optionally, the parasitic infection is a Plasmodium infection (e.g., aPlasmodium falciparum infection). Optionally, the parasitic infection ismalaria. The methods can further comprise administering to the subjectan additional therapeutic agent (e.g., an anti-malarial agent).

Methods of treating or preventing a bacterial infection in a subject arealso described herein. A method of treating or preventing a bacterialinfection in a subject comprises administering to a subject an effectiveamount of a compound or a composition as described herein. The methodscan further comprise administering to the subject an additionaltherapeutic agent (e.g., an anti-bacterial agent).

Also described herein are methods of treating or preventing cancer in asubject. A method of treating or preventing cancer in a subjectcomprises administering to a subject an effective amount of a compoundor a composition as described herein. The methods can further compriseadministering to the subject an additional therapeutic agent (e.g., ananti-cancer agent).

Methods of synthesizing N-(α-peroxy)carbazole compounds are alsoprovided herein. A method of synthesizing an N-(α-peroxy)carbazolecompound comprises reacting a carbonyl compound, a carbazole, and aperoxide in the presence of a catalyst. Optionally, the carbonylcompound is an aldehyde and/or the peroxide is a hydroperoxide. Thecatalyst can be an acid catalyst. Optionally, the reacting step isperformed in the presence of a solvent.

The details of one or more embodiments are set forth in the descriptionbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

DETAILED DESCRIPTION

Provided herein are N-(α-peroxy)carbazole compounds and derivativesthereof and methods for their use. The N-(α-peroxy)carbazole compoundsdescribed herein are useful for treating or preventing parasiticinfections, bacterial infections, and cancer in subjects. The methodsinclude administering an N-(α-peroxy)carbazole compound as describedherein to a subject. Also provided herein are methods for synthesizingN-(α-peroxy)carbazole compounds.

I. Compounds

A class of N-(α-peroxy)carbazole compounds described herein isrepresented by Formula I:

and pharmaceutically acceptable salts and prodrugs thereof.

In Formula I,

is a single bond or a double bond.

Also in Formula I, A¹, A², A³, A⁴, A⁵ , A⁶, A⁷, and A⁸ are eachindependently selected from CR, CR₂, O, SO₂, N, and NR, as appropriatebased on whether

is a single bond or a double bond. For example, when the bond connectingA⁵ to the carbon of the five-membered ring is a double bond, A⁵ can beCR or N. When the bond connecting A⁵ to the carbon of the five-memberedring is a single bond, A⁵ can be CR₂, O, SO₂, or NR. When the bondbetween A⁶ and A⁷ is a double bond, A⁶ and/or A⁷ can be CR or N. Whenthe bond between A⁶ and A⁷ is a single bond, A⁶ and/or A⁷ can be CR₂, O,SO₂, or NR. When the bond connecting A⁸ to the carbon of thefive-membered ring is a double bond, A⁸ can be CR or N. When the bondconnecting A⁸ to the carbon of the five-membered ring is a single bond,A⁸ can be CR₂, O, SO₂, or NR. Each R is selected from the groupconsisting of hydrogen, halogen, cyano, trifluoromethyl, alkoxy,aryloxy, substituted or unsubstituted carbonyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heteroalkenyl, substituted or unsubstitutedheteroalkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocycloalkyl.

Additionally in Formula I, R⁹, R¹⁰, and R¹¹ are each independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedheteroalkenyl, substituted or unsubstituted heteroalkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocycloalkyl.

Optionally, in Formula I, adjacent R groups can be combined to form acyclic compound, e.g., a substituted or unsubstituted aryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted heterocycloalkenyl.

Optionally, A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are each independentlyselected from CR. In these examples, Formula I can be represented byStructure I-A:

In Structure I-A, R¹, R², R³, R⁴, R⁵, R⁶, and R⁸ are each independentlyselected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy,aryloxy, substituted or unsubstituted carbonyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heteroalkenyl, substituted or unsubstitutedheteroalkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocycloalkyl. Optionally, R¹ ishydrogen. Optionally, R² is hydrogen. Optionally, R³ is hydrogen.Optionally, R⁴ is hydrogen. Optionally, R⁵ is hydrogen. R⁶ canoptionally be hydrogen. Optionally, R⁷ is hydrogen. Optionally, R⁸ ishydrogen.

Also in Structure I-A, R⁹, R¹⁰, and R¹¹ are each independently selectedfrom hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstitutedheteroalkenyl, substituted or unsubstituted heteroalkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocycloalkyl. Optionally, R⁹ is substituted orunsubstituted alkyl.

Optionally, R¹⁰ is hydrogen and R¹¹ is t-butyl. In these examples,Formula I can be represented by Structure 1-B:

In Structure 1-B, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are asdescribed above for Structure I-A.

Examples of Structure 1-B include the following compounds:

Optionally, A¹, A², A³, and A⁴ are each independently selected from CR;A⁵, A⁶, and A⁸ are each independently selected from CR₂ and A⁷ is NR. Inthese examples, Formula I can be represented by Structure 1-C:

In Structure 1-C, R¹, R², R³, R⁴, R⁵ , and R⁸ are each independentlyselected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy,aryloxy, substituted or unsubstituted carbonyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heteroalkenyl, substituted or unsubstitutedheteroalkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocycloalkyl.

Also in Structure 1-C, R⁷ is hydrogen, substituted or unsubstitutedcarbonyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstitutedheteroalkenyl, substituted or unsubstituted heteroalkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocycloalkyl.

An example of Structure 1-C includes the following compound:

Optionally, at least one of A¹, A², A³, A⁴, A⁵, A⁶, A⁷, or A⁸ is N. Inthese examples,

Formula I can be represented by Structure 1-D, Structure 1-E, Structure1-F, Structure 1-G, Structure 1-H, Structure 1-I, Structure 1-J, orStructure 1-K:

Optionally, more than one of A¹, A², A³, A⁴, A⁵, A⁶, A⁷, or A⁸ is N.

As used herein, the terms alkyl, alkenyl, and alkynyl include straight-and branched-chain monovalent substituents. Examples include methyl,ethyl, isobutyl, 3-butynyl, and the like. Ranges of these groups usefulwith the compounds and methods described herein include C₁-C₂₀ alkyl,C₂-C₂₀ alkenyl, and C₂-C₂₀ alkynyl. Additional ranges of these groupsuseful with the compounds and methods described herein include C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, and C₂-C₄ alkynyl.

Heteroalkyl, heteroalkenyl, and heteroalkynyl are defined similarly asalkyl, alkenyl, and alkynyl, but can contain O, S, or N heteroatoms orcombinations thereof within the backbone. Ranges of these groups usefulwith the compounds and methods described herein include C₁-C₂₀heteroalkyl, C₂-C₂₀ heteroalkenyl, and C₂-C₂₀ heteroalkynyl. Additionalranges of these groups useful with the compounds and methods describedherein include C₁-C₁₂ heteroalkyl, C₂-C₁₂ heteroalkenyl, C₂-C₁₂heteroalkynyl, C₁-C₆ heteroalkyl, C₂-C₆ heteroalkenyl, C₂-C₆heteroalkynyl, C₁-C₄ heteroalkyl, C₂-C₄ heteroalkenyl, and C₂-C₄heteroalkynyl.

The terms cycloalkyl, cycloalkenyl, and cycloalkynyl include cyclicalkyl groups having a single cyclic ring or multiple condensed rings.Examples include cyclohexyl, cyclopentylethyl, and adamantanyl. Rangesof these groups useful with the compounds and methods described hereininclude C₃-C₂₀ cycloalkyl, C₃-C₂₀ cycloalkenyl, and C₃-C₂₀ cycloalkynyl.Additional ranges of these groups useful with the compounds and methodsdescribed herein include C₅-C₁₂ cycloalkyl, C₅-C₁₂ cycloalkenyl, C₅-C₁₂cycloalkynyl, C₅-C₆ cycloalkyl, C₅-C₆ cycloalkenyl, and C₅-C₆cycloalkynyl.

The terms heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynylare defined similarly as cycloalkyl, cycloalkenyl, and cycloalkynyl, butcan contain O, S, or N heteroatoms or combinations thereof within thecyclic backbone. Ranges of these groups useful with the compounds andmethods described herein include C₃-C₂₀ heterocycloalkyl, C₃-C₂₀heterocycloalkenyl, and C₃-C₂₀ heterocycloalkynyl. Additional ranges ofthese groups useful with the compounds and methods described hereininclude C₅-C₁₂ heterocycloalkyl, C₅-C₁₂ heterocycloalkenyl, C₅-C₁₂heterocycloalkynyl, C₅-C₆ heterocycloalkyl, C₅-C₆ heterocycloalkenyl,and C₅-C₆ heterocycloalkynyl.

Aryl molecules include, for example, cyclic hydrocarbons thatincorporate one or more planar sets of, typically, six carbon atoms thatare connected by delocalized electrons numbering the same as if theyconsisted of alternating single and double covalent bonds. An example ofan aryl molecule is benzene. Heteroaryl molecules include substitutionsalong their main cyclic chain of atoms such as O, N, or S. Whenheteroatoms are introduced, a set of five atoms, e.g., four carbon and aheteroatom, can create an aromatic system. Examples of heteroarylmolecules include furan, pyrrole, thiophene, imadazole, oxazole,pyridine, and pyrazine. Aryl and heteroaryl molecules can also includeadditional fused rings, for example, benzofuran, indole, benzothiophene,naphthalene, anthracene, and quinoline. The aryl and heteroarylmolecules can be attached at any position on the ring, unless otherwisenoted.

The term alkoxy as used herein is an alkyl group bound through a single,terminal ether linkage. The term aryloxy as used herein is an aryl groupbound through a single, terminal ether linkage. Likewise, the termsalkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy,heteroalkynyloxy, heteroaryloxy, cycloalkyloxy, and heterocycloalkyloxyas used herein are an alkenyloxy, alkynyloxy, heteroalkyloxy,heteroalkenyloxy, heteroalkynyloxy, heteroaryloxy, cycloalkyloxy, andheterocycloalkyloxy group, respectively, bound through a single,terminal ether linkage.

The term hydroxy as used herein is represented by the formula —O H.

The terms amine or amino as used herein are represented by theformula-NZ¹Z², where Z¹ and Z² can each be substitution group asdescribed herein, such as hydrogen, an alkyl, halogenated alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group described above.

The alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, orheterocycloalkyl molecules used herein can be substituted orunsubstituted. As used herein, the term substituted includes theaddition of an alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl,heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, orheterocycloalkyl group to a position attached to the main chain of thealkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, orheterocycloalkyl, e.g., the replacement of a hydrogen by one of thesemolecules. Examples of substitution groups include, but are not limitedto, hydroxy, halogen (e.g., F, Br, Cl, or I), and carboxyl groups.Conversely, as used herein, the term unsubstituted indicates the alkoxy,aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, orheterocycloalkyl has a full complement of hydrogens, i.e., commensuratewith its saturation level, with no substitutions, e.g., linear decane(—(CH₂)₉—CH₃).

II. Methods of Making the Compounds

The compounds described herein can be prepared in a variety of ways. Thecompounds can be synthesized using various synthetic methods. At leastsome of these methods are known in the art of synthetic organicchemistry. The compounds described herein can be prepared from readilyavailable starting materials. Optimum reaction conditions can vary withthe particular reactants or solvent used, but such conditions can bedetermined by optimization procedures.

Variations on Formula I include the addition, subtraction, or movementof the various constituents as described for each compound. Similarly,when one or more chiral centers are present in a molecule, all possiblechiral variants are included. Additionally, compound synthesis caninvolve the protection and deprotection of various chemical groups. Theuse of protection and deprotection, and the selection of appropriateprotecting groups can be determined. The chemistry of protecting groupscan be found, for example, in Greene and Wuts, Protective Groups inOrganic Synthesis, 3rd. Ed., Wiley & Sons, 2002, which is incorporatedherein by reference in its entirety.

Reactions to produce the compounds described herein can be carried outin solvents, which can be selected by one of skill in the art of organicsynthesis. Solvents can be substantially nonreactive with the startingmaterials (reactants), the intermediates, or products under theconditions at which the reactions are carried out, i.e., temperature andpressure. Reactions can be carried out in one solvent or a mixture ofmore than one solvent. Product or intermediate formation can bemonitored according to any suitable method known in the art. Forexample, product formation can be monitored by spectroscopic means, suchas nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C) infraredspectroscopy, spectrophotometry (e.g., UV-visible), or massspectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The N-(α-peroxy)carbazole compounds and derivatives thereof according toFormula I can be prepared according to Scheme I shown below.

As shown in Scheme 1, a carbazole or carbazole derivative, a carbonylcompound, and a peroxide are reacted in the presence of a catalyst.Optionally, the carbonyl compound is an aldehyde, including aliphaticaldehydes or aromatic aldehydes, such as isoamyl aldehyde andbenzaldehyde. Optionally, the carbonyl compound is a ketone. Theperoxide can be a hydroperoxide or a protected peroxide, such as atrimethylsilyl (TMS)-protected peroxide. The ratio of indole to carbonylto peroxide can optionally be 1 part indole to 2 parts carbonyl to 3parts peroxide.

The catalyst can be an acid catalyst, such asp-toluenesulfonic acid(PTSA). The reaction can be performed in the presence of a solvent.Suitable solvents include, for example, halogenated solvents, such asdichloromethane, dichloroethane, and chloroform, and other aproticsolvents. The reaction can be performed for a period of time.Optionally, the reaction can be performed for a period up to 24 hours(e.g., 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16hours, 18 hours, 20 hours, 22 hours, or 24 hours, inclusive).

Exemplary methods for synthesizing the compounds as described herein areprovided in Example 1 below.

III. Pharmaceutical Formulations

The compounds described herein or derivatives thereof can be provided ina pharmaceutical composition. Depending on the intended mode ofadministration, the pharmaceutical composition can be in the form ofsolid, semi-solid or liquid dosage forms, such as, for example, tablets,suppositories, pills, capsules, powders, liquids, or suspensions,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include a therapeuticallyeffective amount of the compound described herein or derivatives thereofin combination with a pharmaceutically acceptable carrier and, inaddition, may include other medicinal agents, pharmaceutical agents,carriers, or diluents. By pharmaceutically acceptable is meant amaterial that is not biologically or otherwise undesirable, which can beadministered to an individual along with the selected compound withoutcausing unacceptable biological effects or interacting in a deleteriousmanner with the other components of the pharmaceutical composition inwhich it is contained.

As used herein, the term carrier encompasses any excipient, diluent,filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, orother material well known in the art for use in pharmaceuticalformulations. The choice of a carrier for use in a composition willdepend upon the intended route of administration for the composition.The preparation of pharmaceutically acceptable carriers and formulationscontaining these materials is described in, e.g., Remington: The Scienceand Practice of Pharmacy, 22d Edition, Loyd et al. eds., PharmaceuticalPress and Philadelphia College of Pharmacy at University of the Sciences(2012). Examples of physiologically acceptable carriers include buffers,such as phosphate buffers, citrate buffer, and buffers with otherorganic acids; antioxidants including ascorbic acid; low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers, suchas polyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates, including glucose, mannose, or dextrins; chelatingagents, such as EDTA; sugar alcohols, such as mannitol or sorbitol;salt-forming counterions, such as sodium; and/or nonionic surfactants,such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), polyethylene glycol(PEG), and PLURONICS™ (BASF; Florham Park, N.J.).

Compositions containing the compound described herein or derivativesthereof suitable for parenteral injection may comprise physiologicallyacceptable sterile aqueous or nonaqueous solutions, dispersions,suspensions or emulsions, and sterile powders for reconstitution intosterile injectable solutions or dispersions. Examples of suitableaqueous and nonaqueous carriers, diluents, solvents or vehicles includewater, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol,and the like), suitable mixtures thereof, vegetable oils (such as oliveoil) and injectable organic esters such as ethyl oleate. Proper fluiditycan be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions may also contain adjuvants, such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be promoted by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. Isotonic agents, for example, sugars, sodium chloride, and thelike may also be included. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration of the compounds describedherein or derivatives thereof include capsules, tablets, pills, powders,and granules. In such solid dosage forms, the compounds described hereinor derivatives thereof is admixed with at least one inert customaryexcipient (or carrier), such as sodium citrate or dicalcium phosphate,or (a) fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate, (e) solution retarders, as for example, paraffin, (f)absorption accelerators, as for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol, and glycerolmonostearate, (h) adsorbents, as for example, kaolin and bentonite, and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hardfilled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethyleneglycols, and thelike.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others known in the art. They may contain opacifying agentsand can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions that can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration of the compounds describedherein or derivatives thereof include pharmaceutically acceptableemulsions, solutions, suspensions, syrups, and elixirs. In addition tothe active compounds, the liquid dosage forms may contain inert diluentscommonly used in the art, such as water or other solvents, solubilizingagents, and emulsifiers, as for example, ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils,in particular, cottonseed oil, groundnut oil, com germ oil, olive oil,castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol,polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures ofthese substances, and the like.

Besides such inert diluents, the composition can also include additionalagents, such as wetting, emulsifying, suspending, sweetening, flavoring,or perfuming agents.

Suspensions, in addition to the active compounds, may contain additionalagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions of the compounds described herein or derivatives thereoffor rectal administrations are optionally suppositories, which can beprepared by mixing the compounds with suitable non-irritating excipientsor carriers, such as cocoa butter, polyethyleneglycol or a suppositorywax, which are solid at ordinary temperatures but liquid at bodytemperature and, therefore, melt in the rectum or vaginal cavity andrelease the active component.

Dosage forms for topical administration of the compounds describedherein or derivatives thereof include ointments, powders, sprays, andinhalants. The compounds described herein or derivatives thereof areadmixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, ointments, powders, and solutions arealso contemplated as being within the scope of the compositions.

The compositions can include one or more of the compounds describedherein and a pharmaceutically acceptable carrier. As used herein, theterm pharmaceutically acceptable salt refers to those salts of thecompound described herein or derivatives thereof that are, within thescope of sound medical judgment, suitable for use in contact with thetissues of subjects without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible, of the compounds described herein. The term saltsrefers to the relatively non-toxic, inorganic and organic acid additionsalts of the compounds described herein. These salts can be prepared insitu during the isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate,glucoheptonate, lactobionate, methane sulphonate, and laurylsulphonatesalts, and the like. These may include cations based on the alkali andalkaline earth metals, such as sodium, lithium, potassium, calcium,magnesium, and the like, as well as non-toxic ammonium, quaternaryammonium, and amine cations including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. (See S. M.Barge et al., J. Pharm. Sci. (1977) 66, 1, which is incorporated hereinby reference in its entirety, at least, for compositions taughttherein.)

Administration of the compounds and compositions described herein orpharmaceutically acceptable salts thereof can be carried out usingtherapeutically effective amounts of the compounds and compositionsdescribed herein or pharmaceutically acceptable salts thereof asdescribed herein for periods of time effective to treat a disorder. Theeffective amount of the compounds and compositions described herein orpharmaceutically acceptable salts thereof as described herein may bedetermined by one of ordinary skill in the art and includes exemplarydosage amounts for a mammal of from about 0.5 to about 200 mg/kg of bodyweight of active compound per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1 to 4times per day. Alternatively, the dosage amount can be from about 0.5 toabout 150 mg/kg of body weight of active compound per day, about 0.5 to100 mg/kg of body weight of active compound per day, about 0.5 to about75 mg/kg of body weight of active compound per day, about 0.5 to about50 mg/kg of body weight of active compound per day, about 0.01 to about50mg/kg of body weight of active compound per day, about 0.05 to about25 mg/kg of body weight of active compound per day, about 0.1 to about25 mg/kg of body weight of active compound per day, about 0.5 to about25 mg/kg of body weight of active compound per day, about 1 to about 20mg/kg of body weight of active compound per day, about 1 to about 10mg/kg of body weight of active compound per day, about 20mg/kg of bodyweight of active compound per day, about 10 mg/kg of body weight ofactive compound per day, about 5 mg/kg of body weight of active compoundper day, about 2.5 mg/kg of body weight of active compound per day,about 1.0 mg/kg of body weight of active compound per day, or about 0.5mg/kg of body weight of active compound per day, or any range derivabletherein. Optionally, the dosage amounts are from about 0.01 mg/kg toabout 10 mg/kg of body weight of active compound per day. Optionally,the dosage amount is from about 0.01 mg/kg to about 5 mg/kg. Optionally,the dosage amount is from about 0.01 mg/kg to about 2.5 mg/kg.

The specific dose level and frequency of dosage for any particularsubject may be varied and will depend upon a variety of factors,including the activity of the specific compound employed, the metabolicstability and length of action of that compound, the species, age, bodyweight, general health, sex and diet of the subject, the mode and timeof administration, rate of excretion, drug combination, and severity ofthe particular condition.

The precise dose to be employed in the formulation will also depend onthe route of administration, and the seriousness of the disease ordisorder, and should be decided according to the judgment of thepractitioner and each subject's circumstances. Effective doses can beextrapolated from dose-response curves derived from in vitro or animalmodel test systems. Further, the route of administration will determinethe doses that result in a plasma concentration for a desired level ofresponse in the cells, tissues and/or organs of a subject.

IV. Methods of Use

Provided herein are methods to treat, prevent, or ameliorate parasiticinfections, bacterial infections, and/or cancer in a subject. Themethods include administering to a subject an effective amount of one ormore of the compounds or compositions described herein or apharmaceutically acceptable salt or prodrug thereof. The method caninclude selecting a subject with a parasitic infection, a bacterialinfection, or cancer, using methods within the art. The expression“effective amount,” when used to describe an amount of compound in amethod, refers to the amount of a compound that achieves the desiredpharmacological effect or other effect, for example, an amount thatresults in infection reduction or tumor growth rate reduction. Thecompounds and compositions described herein or pharmaceuticallyacceptable salts thereof are useful for treating parasitic infections,bacterial infections, and/or cancer in humans, including, withoutlimitation, pediatric and geriatric populations, and in animals, e.g.,veterinary applications.

Optionally, the parasitic infection is a Plasmodium infection, such as aPlasmodium falciparum infection. Optionally, the parasitic infection ismalaria. Optionally, the parasitic infection is a Toxoplarma gondiiinfection, a Leishmania infection, or a Babesia infection.

Optionally, the bacterial infection is a Gram-negative bacterialinfection, such as an Acinetobacter infection (e.g., an Acinetobacterbaumannii infection), a Pseudomonas infection (e.g., a Pseudomonasaeruginosa infection), a Klebsiella infection, an Escherichia infection,a Salmonella infection, a Yersinia infection, a Shigella infection, aProteus infection, an Enterobacter infection, a Serratia infection, or aCitrobacter infection. In some examples, the microbial infection is aGram-positive bacterial infection, such as a Bacillus infection, aListeria infection, a Staphylococcus infection, a Streptococcusinfection, an Enterococcus infection, or a Clostridium infection.

Optionally, the cancer is bladder cancer, brain cancer, breast cancer,colorectal cancer (e.g., colon cancer, rectal cancer), cervical cancer,chondrosarcoma, endometrial cancer, gastrointestinal cancer, gastriccancer, genitourinary cancer, head and neck cancer, hepatocellularcarcinoma, liver cancer, lung cancer, ovarian cancer, pancreatic cancer,prostate cancer, renal cancer, skin cancer, or testicular cancer.

The method of treating or preventing parasitic infections, bacterialinfections, and/or cancer in a subject can further compriseadministering to the subject one or more additional therapeutic agents.The one or more additional agents and the compounds described herein orpharmaceutically acceptable salts or prodrugs thereof can beadministered in any order, including concomitant, simultaneous, orsequential administration. Sequential administration can be temporallyspaced order of up to several days apart. The methods can also includemore than a single administration of the one or more additional agentsand/or the compounds described herein or pharmaceutically acceptablesalts or prodrugs thereof. The administration of the one or moreadditional agents and the compounds described herein or pharmaceuticallyacceptable salts or prodrugs thereof can be by the same or differentroutes and concurrently or sequentially.

Therapeutic agents include, but are not limited to, antimalarial agents.An antimalarial agent is a compound or composition effective ininhibiting or arresting the activity of a Plasmodium parasite. Suitableantimalarial agents include, for example, chloroquine, quinine,mefloquine, amodiaquin, primaquine, pyrimethamine, sulfonamides,sulfones, dihydrofolate reductase inhibitors, and tetrandine.

Antibacterial agents can also be used as the therapeutic agents.Suitable antibacterial agents can include any agent effective fortreating a bacterial infection and include, for example, tetracyclines(e.g., minocycline), quinolones (e.g., ciprofloxacin, levofloxacin, andnalidixic acid), aminoglycosides (e.g., amikacin, gentamycin, kanamycin,and tobramycin), carbapenems (e.g., meropenem), cephalosporins (e.g.,ceftriaxone), macrolides (e.g., erythromycin), polypeptides (e.g.,colistin and polymxin B), sulfonamides (e.g., sulfamethoxazole),glycylcyclines (e.g., tigecycline), beta lactams (e.g., penams),lipopeptides (e.g., daptomycin), oxazolidinones (e.g., linezolid), andtrimethoprim.

Therapeutic agents further include, but are not limited to,chemotherapeutic agents. A chemotherapeutic agent is a compound orcomposition effective in inhibiting or arresting the growth of anabnormally growing cell. Thus, such an agent may be used therapeuticallyto treat cancer as well as other diseases marked by abnormal cellgrowth. Illustrative examples of chemotherapeutic compounds include, butare not limited to, bexarotene, gefitinib, erlotinib, gemcitabine,paclitaxel, docetaxel, topotecan, irinotecan, temozolomide, carmustine,vinorelbine, capecitabine, leucovorin, oxaliplatin, bevacizumab,cetuximab, panitumumab, bortezomib, oblimersen, hexamethylmelamine,ifosfamide, CPT-11, deflunomide, cycloheximide, dicarbazine,asparaginase, mitotant, vinblastine sulfate, carboplatin, colchicine,etoposide, melphalan, 6-mercaptopurine, teniposide, vinblastine,antibiotic derivatives (e.g. anthracyclines such as doxorubicin,liposomal doxorubicin, and diethylstilbestrol doxorubicin, bleomycin,daunorubicin, and dactinomycin); antiestrogens (e.g., tamoxifen);antimetabolites (e.g., fluorouracil (FU), 5-FU, methotrexate,floxuridine, interferon alpha-2B, glutamic acid, plicamycin,mercaptopurine, and 6-thioguanine); cytotoxic agents (e.g., carmustine,BCNU, lomustine, CCNU, cytosine arabinoside, cyclophosphamide,estramustine, hydroxyurea, procarbazine, mitomycin, busulfan, cisplatin,vincristine and vincristine sulfate); hormones (e.g.,medroxyprogesterone, estramustine phosphate sodium, ethinyl estradiol,estradiol, megestrol acetate, methyl testosterone, diethylstilbestrol diphosphate, chlorotrianisene, and testolactone); nitrogen mustardderivatives (e.g., mephalen, chlorambucil, mechlorethamine (nitrogenmustard) and thiotepa); and steroids (e.g., bethamethasone sodiumphosphate).

The methods and compounds as described herein are useful for bothprophylactic and therapeutic treatment. For prophylactic use, atherapeutically effective amount of the compounds and compositions orpharmaceutically acceptable salts thereof as described herein areadministered to a subject prior to onset (e.g., before obvious signs ofa parasitic infection, a bacterial infection, or cancer), during earlyonset (e.g., upon initial signs and symptoms of a parasitic infection, abacterial infection, or cancer), or after the development of a parasiticinfection, a bacterial infection, or cancer. Prophylactic administrationcan occur for several days to years prior to the manifestation ofsymptoms of a parasitic infection, a bacterial infection, or cancer.Therapeutic treatment involves administering to a subject atherapeutically effective amount of the compounds and compositions orpharmaceutically acceptable salts thereof as described herein after aparasitic infection, a bacterial infection, or cancer is diagnosed.

V. Kits

Also provided herein are kits for treating or preventing parasiticinfections, bacterial infections, and/or cancer in a subject. A kit caninclude any of the compounds or compositions described herein. Forexample, a kit can include a compound of Formula I. A kit can furtherinclude one or more additional agents, such as one or moreanti-malarial, anti-bacterial, or anti-cancer agents. A kit can includean oral formulation of any of the compounds or compositions describedherein. A kit can include an intravenous formulation of any of thecompounds or compositions described herein. A kit can additionallyinclude directions for use of the kit (e.g., instructions for treating asubject), a container, a means for administering the compounds orcompositions (e.g., a syringe), and/or a carrier. A kit can includemultiple metered dosages for a course of treatment with the compound ofFormula I, with or without any additional therapeutic agents.

As used herein the terms treatment, treat, or treating refer to a methodof reducing one or more symptoms of an infection, disease, or condition.Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of oneor more symptoms of the infection, disease, or condition. For example, amethod for treating an infection, disease, or condition is considered tobe a treatment if there is a 10% reduction in one or more symptoms orsigns of the infection, disease, or condition in a subject as comparedto a control. As used herein, control refers to the untreated infection,disease, or condition. Thus the reduction can be a 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10%and 100% as compared to native or control levels. It is understood thattreatment does not necessarily refer to a cure or complete ablation ofthe infection, disease, condition, or symptoms of the infection, diseaseor condition.

As used herein, the terms prevent, preventing, and prevention of aninfection, disease, or disorder refer to an action, for example,administration of a composition or therapeutic agent, that occurs beforeor at about the same time a subject begins to show one or more symptomsof the infection, disease, or disorder, which inhibits or delays onsetor severity of one or more symptoms of the infection, disease, ordisorder. For example, the method is considered to be a prevention ifthere is a reduction or delay in onset, incidence, severity orrecurrence of infection or cancer, or one or more symptoms of infection(e.g., fever, chills, vomiting, or convulsions) or cancer (e.g., tumorgrowth) in a subject susceptible to infection or cancer compared tocontrol subjects susceptible to infection or cancer that did not receivea compound as described herein. The reduction or delay in onset,incidence, severity, or recurrence of infection or cancer can be a 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reductionin between 10% and 100% as compared to native or control levels.

As used herein, references to decreasing, reducing, or inhibitinginclude a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% orgreater as compared to a control level. Such terms can include, but donot necessarily include, complete elimination.

As used herein, subject means both mammals and non-mammals. Mammalsinclude, for example, humans; non-human primates, e.g., apes andmonkeys; cattle; horses; sheep; rats; mice; pigs; and goats. Non-mammalsinclude, for example, fish andbirds.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application.

The examples below are intended to further illustrate certain aspects ofthe methods and compositions described herein, and are not intended tolimit the scope of the claims.

EXAMPLES Example 1: Synthesis of Compounds

General Experimental Procedures:

All reagents and solvents were purchased at the highest commercialquality and used as received unless otherwise specified. Reactions werecarried out in an open flask without inert protection, unless otherwisenoted. Analytical thin-layer chromatography (TLC) was performed on 0.25mm coated silica gel plates (60F-254) purchased from Qingdao HaiyangChemical Co., Ltd and visualized by exposure to UV light (254 nm) orstained with potassium permanganate (KMnO₄) and ethanolicphosphomolybdic acid (PMA). ¹H NMR spectra were acquired on a BrukerAVANCE (at 400 MHz, 500 MHz, or 600 MHz) and chemical shifts arereported relative to the residual solvent peak. The followingabbreviations were used to describe the data of ¹H NMR spectra: chemicalshift (δ ppm), s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,br=broad; coupling constant(s) in Hz. ¹³C NMR spectra were acquired on aBruker AVANCE (at 100 MHz, 125 MHz, or 150 MHz) and chemical shifts (δppm) are reported relative to the residual solvent peak. High-resolutionmass spectrometry (HRMS) data were acquired using Bruker MALDI TOF orBrukerDaltonicsMicroTOF-Q-11 Mass Spectrometer.

Preparation of anhydrous tert-butyl hydroperoxide (tBuOOH)

Commercial 70% aqueous tBuOOH (50 mL) was added into 200 mL anhydrousdiethyl ether, and was slowly shaken. The mixture was separated via aseparating funnel. The organic phase was washed twice with 30 mL of asaturated NaCl solution and dried with anhydrous MgSO₄. Removal ofdiethyl ether by vacuum rotation evaporation gave anhydrous tBuOOH,which could be stored at low temperature (<−20° C.).

Standard procedure for the synthesis of N-(α-peroxy)-carbazole

To a stirred solution of carbazole (1.0 mmol), carbonyl (2.0 mmol), andhydroperoxide (3 mmol) in CH₂Cl₂ (5 mL) in an open 25 mL glass flask atroom temperature was added p-toluenesulfonic acid monohydrate (PTSA-H₂O,10 mol %) as solid in one portion. The reaction mixture changed colorimmediately and the reaction generally finished within a few seconds.However, to be more practically convenient, and for aromatic aldehydes,the reaction was allowed to continue, followed by stirring for 5minutes. Then, the reaction mixture was neutralized with NaHCO₃ (aq.),extracted with CH₂Cl₂, and washed by saturated brine. The organic phasewas dried with MgSO₄, followed by vacuum rotation evaporation, to removethe solvent. Purification by flash column chromatography (EtOAc/hexane)on silica gel gave the titled product.

Synthetic Procedures and Characterization for Compounds 1-4:

To a stirred solution of 9H-carbazole (167 mg, 1 mmol), acetaldehyde (88mg, 2 mmol), and tBuOOH (5.5 M solution in decane, 0.6 ml) in CH₂Cl₂ (5mL) in an 25 mL glass flask at room temperature was added PTSA (17 mg,0.1 mmol) in one portion. After stirring for 2 minutes at roomtemperature under air, the reaction mixture was neutralized with NaHCO₃(aq.), and extracted with CH₂Cl₂ (3×10 mL). The organic phase wascollected and dried over anhydrous MgSO₄, followed by vacuum rotationevaporation to remove the solvent. The crude product was then purifiedby flash column chromatography (EtOAc/hexane 1:8 v/v) to give Compound1, 275 mg in 97% yield, as a colorless, crystalline solid. ¹H NMR (600MHz, CDCl₃) δ 8.10-8.09 (d, J=7.7 Hz, 2H), 7.65-7.64 (d, J=7.7 Hz, 2H),7.47-7.44 (t, J=7.4 Hz, 15.3Hz 2H), 7.28-7.25 (t, J=7.4 Hz, 15.3 Hz,2H), 6.49-6.46 (q, 1H), 1.87-1.86 (d, J=6.5 Hz, 3H), 1.07 (s, 9H); ¹³CNMR (125 MHz, CDCl₃) δ 139.55, 125.54, 123.64, 120.13, 119.36, 110.83,84.79, 80.78, 26.28, 17.16 ppm. HRMS (m/z): calculated for C₁₈H₂₂NO₂[M+H]⁺ 284.1645; found 284.1645.

Compound 2 was prepared using the procedure described above forCompound 1. The product was obtained as a colorless, crystalline solid,282 mg, 95% yield. Hexane: EtOAc 8:1. ¹H NMR (400 MHz, CDCl₃) δ8.21-8.19 (d, J=7.7 Hz, 2H), 7.75-7.73 (d, J=7.7 Hz, 2H), 7.56-7.52 (t,J=7.4 Hz, 15.3 Hz 2H), 7.37-7.34 (t, J=7.4 Hz, 15.3 Hz, 2H), 6.35-6.31(t, J=6.8 Hz, 14.5 Hz, IH), 2.46-2.36 (m, 2H), 1.18 (s, 9H), 0.99-0.96(t, J=7.5 Hz, 15.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 139.85, 125.49,123.52, 120.08, 119.28, 110.78, 89.99, 80.76, 26.31, 24.49, 10.02 ppm.HRMS (m/z): calculated for C₁₉H₂₄NO₂ [M+H]⁺ 298.1802; found 298.1805.

Compound 3 was prepared using the procedure described above forCompound 1. The product was obtained as a colorless, crystalline solid,336 mg, 95% yield, Hexane: EtOAc 8:1. ¹H NMR (500 MHz, CDCl₃) δ8.09-8.08 (d, J=7.7 Hz, 2H), 7.62-7.61 (d, J=7.7 Hz, 2H), 7.45-7.42 (t,J=7.4 Hz, 15.0 Hz, 2H), 7.26-7.23 (t, J=7.4 Hz, 15.0 Hz, 2H), 6.28-6.28(t, J=7.2 Hz, 10 14.3 Hz, IH), 2.32-2.19 (m, 2H), 1.39-1.18 (m, 8H),1.05 (s, 9H), 0.82-0.80 (t, J=6.8 Hz, 14.0 Hz, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 139.78, 125.50, 123.54, 120.09, 119.26, 110.76, 88.81, 80.75,31.43, 31.17, 28.85, 26.34, 25.56, 22.44, 13.94 ppm. HRMS (m/z):calculated for C₂₃H₃₂NO₂ [M+H]⁺ 354.2428; found 354.2430.

Compound 4 was obtained using a similar procedure as used forCompound 1. A 0.3 mmol scale based on the carbazole derivative was used,and an off-white solid (115 mg) was obtained, 75% yield, dr=1:1. Hexane:EtOAc 2:1. ¹H NMR (500 MHz, CDCl₃) δ 7.56-7.47 (m, 4H), 7.18-7.09 (m,2H), 6.82-6.80 (d, J=IO Hz, IH), 5.71 (b, IH), 5.45-5.39 (d, IH),4.54-4.51 20 (m, IH), 4.14-3.93 (m, 2H), 3.62-3.44 (m, 2H), 2.91-2.86(m, IH), 2.51-2.46 (m, IH), 2.29-1.64 (m, 7H), 1.26-0.89 (m, 15H); ¹³CNMR (100 MHz, CDCl₃) δ 167.66, 164.80, 163.80, 138.96, 133.66, 132.36,130.89, 130.86, 128.82, 128.78, 127.57, 122.16, 121.82, 119.74, 118.30,118.22, 87.65, 80.71, 71.78, 59.35, 53.77, 47.24, 44.96, 41.11, 30.13,28.39, 27.70, 26.37, 26.25, 25.98, 25.70, 22.99, 22.26, 21.52, 19.41,19.14 ppm. HRMS (m/z): calculated for C₃₀H₄₂N₃O₄ [M+H]⁺ 508.3170; found508.3171.

The compounds and methods of the appended claims are not limited inscope by the specific compounds and methods described herein, which areintended as illustrations of a few aspects of the claims and anycompounds and methods that are functionally equivalent are within thescope of this disclosure. Various modifications of the compounds andmethods in addition to those shown and described herein are intended tofall within the scope of the appended claims. Further, while onlycertain representative compounds, methods, and aspects of thesecompounds and methods are specifically described, other compounds andmethods are intended to fall within the scope of the appended claims.Thus, a combination of steps, elements, components, or constituents canbe explicitly mentioned herein; however, all other combinations ofsteps, elements, components, and constituents are included, even thoughnot explicitly stated.

What is claimed is:
 1. A method of synthesizing anN-(alphα-peroxy)carbazole compound, comprising: reacting, in thepresence of a catalyst, a carbonyl compound; a carbazole or carbazolederivative; and a peroxide.
 2. The method of claim 1, wherein thecarbonyl compound comprises an aldehyde or ketone.
 3. The method ofclaim 2, wherein the carbonyl compound is an aldehyde selected from thegroup consisting of acetaldehyde, isoamyl aldehyde and benzaldehyde. 4.The method of claim 1, wherein the peroxide comprises a hydroperoxide ora protected peroxide.
 5. The method of claim 4, wherein the peroxide isa trimethylsilyl (TMS)-protected peroxide.
 6. The method of claim 4,wherein the peroxide is anhydrous tert-Butyl hydroperoxide.
 7. Themethod of claim 1, wherein the catalyst comprises an acid catalyst. 8.The method of claim 7, wherein the acid catalyst is p-Toluenesulfonicacid.
 9. The method of claim 1, wherein the reacting step is performedin the presence of a solvent.
 10. The method of claim 9, wherein thesolvent is a halogenated or aprotic solvent.
 11. The method of claim 9,wherein the solvent comprises decane and dichloromethane.
 12. The methodof claim 1, wherein the reacting step is performed for a period up to 24hours.
 13. The method of claim 1, wherein the method comprises reactingaccording to Scheme 1:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independentlyselected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy,aryloxy, substituted or unsubstituted carbonyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heteroalkenyl, substituted or unsubstitutedheteroalkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocycloalkyl; and R⁹, R¹⁰, and R¹¹ areeach independently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heteroalkenyl, substituted or unsubstitutedheteroalkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocycloalkyl.
 14. The method of claim13, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen.
 15. Themethod of claim 14, wherein R⁹ is a substituted or unsubstituted alkyl.16. The method of claim 13, wherein R¹⁰ is hydrogen and R¹¹ is t-butyl.17. The method of claim 16, wherein R⁹ is methyl, ethyl or hexyl. 18.The method of claim 1, wherein the carbazole derivative is reacted withthe peroxide and the carbonyl compound, wherein the carbonyl compound isacetaldehyde, the peroxide is tert-Butyl hydroperoxide, and thecarbazole derivative has the following structure: